Severe forms of influenza infections admitted in intensive care units: Analysis of mortality factors

Abstract Background The severe forms of influenza infection requiring intensive care unit (ICU) admission remain a medical challenge due to its high mortality. New H1N1 strains were hypothesized to increase mortality. The studies below represent a large series focusing on ICU‐admitted influenza patients over the last decade with an emphasis on factors related to death. Methods A retrospective study of patients admitted in ICU for influenza infection over the 2010–2019 period in Réunion Island (a French overseas territory) was conducted. Demographic data, underlying conditions, and therapeutic management were recorded. A univariate analysis was performed to assess factors related to ICU mortality. Results Three hundred and fifty adult patients were analyzed. Overall mortality was 25.1%. Factors related to higher mortality were found to be patient age >65, cancer history, need for intubation, early intubation within 48 h after admission, invasive mechanical ventilation (MV), acute respiratory distress syndrome (ARDS), vaso‐support drugs, extracorporal oxygenation by membrane (ECMO), dialysis, bacterial coinfection, leucopenia, anemia, and thrombopenia. History of asthma and oseltamivir therapy were correlated with a lower mortality. H1N1 did not impact mortality. Conclusion Patient's underlying conditions influence hospital admission and secondary ICU admission but were not found to impact ICU mortality except in patients age >65, history of cancer, and bacterial coinfections. Pulmonary involvement was often present, required MV, and often evolved toward ARDS. ICU mortality was strongly related to ARDS severity. We recommend rapid ICU admission of patients with influenza‐related pneumonia, management of bacterial coinfection, and early administration of oseltamivir.


| Statistical analysis
Prognostic factors for mortality were analyzed using the chi-squared test with Fisher's exact test correction, if needed. A p value < 0.05 was considered statistically significant.
The relative risk (RR) for outcome was defined according to the following variables: age (>65 or <65 years), obesity (BMI > 30 or
The univariate analysis recorded variables related to death are listed in Table 3. The univariate analysis identified the following variables as potential prognostic risk factors of death: age over 65, history of cancer, SAPS II score over 40, intubation during stay and within the first 48 h after admission, vaso-drug support, ARDS, requirement of ECMO, dialysis, bacterial coinfections, leucocytes <2.5 G/L, hemoglobin <8 g/dL, and platelets <50 G/L. Asthma and oseltamivir treatment were found to be a protective factor. and age over 65 years are considered as recognized risk factors for developing a severe influenza disease. 8,9 The literature is consistent and emphasizes that the presence of one of these factors is related with an increased risk for hospitalization. [8][9][10] The characteristics of the population in Réunion Island is slightly dif- In the present study, three factors increasing ICU mortality were found. Age >65 years was statistically related with mortality.

| DISCUSSION
T A B L E 3 Univariate analysis for clinical factors, therapeutic issues, and laboratory findings in surviving versus non-surviving patients in ICU. On the other hand, asthma was found as a protective factor. The mean age of asthmatics was 55.9 years of age and was not different from the overall study population. Twenty-four of them were over 65 years of age (38%). In other studies, asthma was considered as a pejorative factor for hospitalization. 17 COPD and asthma were frequent in our study population, but smoking habits and smokingrelated COPD were not found as independent factors for death.

The impact of therapy based on inhaled corticosteroids (ICS)
widely used in asthma patients could be the reason for our finding.
Recently, attention has been drawn on a potential protective effect of ICS in asthmatic patients with SARS COV-2 infection, 18 and a recent meta-analysis confirmed the absence of increased risk for influenza and safety profile for asthmatics with regular use of ICS. 19 Considering all the usual underlying conditions described in the study, the analysis of the literature confirmed that these factors are generally related with an increase for hospitalization in medical wards and secondary ICU admissions. 20,21 The specific impact on ICU's outcome is less evident and requires larger series.
Information about influenza vaccination was only available in 96 (27%) of patients. Among these patients, only 16 were vaccinated within the previous 12 months. Due to this small number, statistical analysis did not show any benefit. From a public health standpoint, influenza vaccination is therefore highly recommended in these populations. 8,10 The primary objective of this large study was to analyze patient's severity at the time of ICU admission and its evolution during the ICU stay.
We observed a crude mortality in the ICU of 25.1%. There are few studies analyzing the mortality in ICU-admitted patients with severe influenza infection.
An old meta-analysis found a wide range of crude mortality from 14% to 71%. 22  Bacterial coinfection is frequent in patients with influenza and was reported between 11% and 35%. 21 The results confirm the high frequency of bacterial coinfections and were related to a mortality increase. 30 Surprisingly, coinfection with either S. aureus or pneumococcus pneumoniae strains was not statistically correlated with mortality. Considering these results, it is advised to diagnose the presence of bacterial coinfections at admission in hospital and in the ICU to avoid delaying the introduction of effective antibiotic therapy.
As the study was of a retrospective nature, the limitations due to data collection are acknowledged. A lack of information is important for BMI and vaccination status. In life-threatening situation, information on height and weight may not be systematically recorded. History of influenza vaccination is sometimes difficult to assess in ICU due to patient's condition and family questioning. For chronic diseases, compliance to daily therapy is impossible to assess. Patient's underlying conditions may be imprecise and may explain discrepancies in the results compared to literature. During hospitalization, the exact timing of starting oseltamivir was difficult to record, but the majority of patients were rapidly admitted to the ICU, and oseltamivir was early administered.

| CONCLUSION
In summary, a large cohort of ICU-admitted patients for severe influenza disease over 10 years was analyzed. The overall mortality was 25.1%. The predominant clinical presentation was a specific pulmonary involvement rapidly requiring MV and often evolving toward ARDS. Timely ICU admission for patients with severe influenza is recommended and as early as possible in the case of respiratory failure in order to enable effective intensive care.
Patient's underlying conditions are important to consider. Most of them are factors that influence hospital admission and secondary ICU admission and were not found to impact specific ICU mortality. In the study of ICU-admitted patients presenting with severe influenza, patient age >65 years, history of cancer, and bacterial coinfections were identified as the three pejorative prognostic factors. Influenza vaccination remains important to promote in the community for elderly people and patients with comorbidities.

AUTHOR CONTRIBUTIONS
Victor Verdier collected the data and wrote the manuscript. Fabrice Paganin analyzed the data and wrote the manuscript. Francois Lilienthal, Arnaud Desvergez, Arnaud Winer, and Virgile Gazaille wrote the manuscript. All the authors contributed equally.